APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses

Abstract

Accumulation of amyloid-β peptides (Aβ), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer's disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.

APP Receptor? To Be or Not To Be

“…Recently, it has been shown that soluble APP and the APP-E1 domain could activate the Akt survival pathway following trophic factor depletion and that this activation involves an interaction of APP or APP-E1 domain with APP-FL [152] . In a similar fashion, Aβ interaction with APP induces G-protein-dependent enhancement of synaptic activity that involves the APP-E1 domain [153] . As previously discussed in section 1, APP-FL possesses the structural ability to bind ligand to its own E1 domain.…”

“…As previously discussed in section 1, APP-FL possesses the structural ability to bind ligand to its own E1 domain. This association could initiate subsequent G-protein coupled signaling events by engaging motifs within the cytosolic C-terminal tail of APP [152, 153] . This scenario is reminiscent of a complex formation between a ligand and an autoreceptor.…”

“…Based on these interactions, some of these matrix proteins have been considered as candidate ligands for APP including soluble APP [65] and Aβ per se [153, 171, 172] , F-spondin [170] , reelin [173] , lingo-1 [151] , contactins [151, 174, 175] , β1 integrin [64, 173] , and pancortin [175, 176] . Among these, reelin, lingo-1, and pancortin-1 were found to significantly inhibit APP ectodomain shedding, suggesting their roles as physiological modulators of APP processing or APP secretase activity per se [175] .…”

Impairments of neural circuit function in Alzheimer's disease

“…Remaining open questions concern the cellular mechanisms by which soluble Ab species induce neuronal hyperactivity and which of their various forms are most toxic. For instance, Ab dimers were shown to reduce the re-uptake of synaptic glutamate [42] and Ab 1 -40 monomers and dimers were found to enhance the presynaptic release of glutamate [43]. A combination of these effects could increase extracellular levels of residual glutamate and, thereby, promote neuronal hyperactivity.…”

Synaptic Function and Dysfunction in Alzheimer’s Disease

“…Elevated electrical activity in the hippocampus has been observed early in AD in stages preceding the formation of senile plaques [107]. Interestingly, a recent paper suggested that APP molecules may function as surface receptors modulating the Aβ signaling [108]; the Authors showed that neurons in hippocampus became hyperactive at the pre-synaptic site through APP homodimer as pre-synaptic receptor, which binds Aβ40 following a rise in its concentration. If very low Aβ level is essential for the normal dayto-day life in agreement to Puzzo et al [66,67], thus, we can hypothesize that when the level of Aβ peptides is even slightly increased, it causes neuronal hyperactivity and neuronal functional impairment in several brain areas as also frequently reported in MCI patients [109].…”